Clinical approach to polyuria (Proceedings)

Dogs and cats frequently present for signs related to the urinary tract. These signs may be due to inappropriate urination (house soiling or urinary incontinence) or may relate to the act of voiding itself. Voiding disorders include abnormalities in frequency, duration and volume of urine produced. Polyuria refers to an increase in the amount of urine produced (> 50 ml/kg/day). It is difficult to impossible to discuss polyuria without also discussing polydipsia, or increased water consumption. Polydipsia is defined as water consumption greater than 100 ml/kg/day in the dog and cat. These two disorders occur together in most instances. Depending on the etiology you might see a primary polydipsia with a secondary polyuria or a primary polyuria with a secondary polydipsia.

Urinary water losses are regulated by vasopressin and the kidneys ability to respond to this hormone. Central and peripheral osmoreceptors and baroreceptors respond to increases in plasma osmolality (primarily sodium) and decreases in blood pressure by stimulating vasopressin release and thirst. Vasopressin then acts on the kidneys by inserting water channels into the distal tubules and collecting ducts of the nephron. The osmotic pull from the renal medullary interstitium then pulls water out of the tubules producing a more concentrated urine. Activation of the renin-angiotensin-aldosterone system also plays a lesser role. The kidneys sense a decrease in blood volume and produce renin which results in the eventual production of angiotensin II. Angiotensin II, in addition to being a potent vasoconstrictor, also stimulates the thirst center and vasopressin release. It is now easy to see how a decrease in production or renal responsiveness to vasopressin as well as changes in the renal tubular:medullary gradient can lead to polyuria.

Causes of primary & secondary polyuria

Disorders that produce a primary polyuria cause an initial increase in urine production most often accompanied by an increase in water consumption. An osmotic diuresis can cause a primary polyuria by increasing the amount of solutes in the urine. This increase in tubular solute concentration competes with the medullary solute concentration for water. More common disorders resulting in high urine solutes include chronic kidney disease, diabetes mellitus, diabetic ketoacidosis, and relief of a urinary tract obstruction. Less common causes of increased solutes are mannitol administration and primary renal glycosuria.

Disorders that interfere with the renal tubular response to vasopressin (antidiuretic hormone) also cause polyuria. Common disorders include excess glucocorticoids (exogenous or endogenous), hyperthyroidism, hypercalcemia, liver disease, pyelonephritis, hypoadrenocorticism, septicemia, Escherichia coli infection, and pyometra. Less common disorders include primary hyperaldosteronism, hypokalemia, acromegaly, polycythemia, central diabetes insipidus, and primary nephrogenic diabetes insipidus.

Additional causes of polyuria include loss of a functional medullary gradient which can occur as a result of any of the disorders that causes polyuria and polydipsia as well as with fluid administration.

Disorders that cause an initial polydipsia and secondary polyuria include excess glucocorticoids (decrease vasopressin rlease) and psychogenic polydipsia. Hepatic insufficiency may cause a primary polydipsia as well.

Causes of polyuria and polydipsia

Drugs

     o Anticonvulsants

     o Glucocorticoids

     o Diuretics (loop, thiazide)

Endocrine disorders

     o Diabetes mellitus

     o Hyperadrenocorticism

     o Hyperthyroidism

     o Hypoadrenocorticism

     o Hyperaldosteronism

     o Acromegaly

     o Central diabetes insipidus

Urinary tract disorders

     o Chronic kidney disease

     o Pyelonephritis

     o Urinary tract obstruction

     o Primary renal glycosuria

     o Primary nephrogenic diabetes insipidus

Electrolyte abnormalities

     o Hypercalcemia

     o Hypokalemia

Infection

     o Pyometra

     o Escherichia coli

     o Septicemia

Miscellaneous

     o Hepatic disease

     o Paraneoplastic

     o Psychogenic polydipsia

     o Polycythemia

     o Diet – low protein

Diagnostic evaluation

It is important to distinguish true polyuria from lower urinary tract disease because the differentials and diagnostic work up are very different. This can usually be accomplished through a careful review of the history as well as a urinalysis. As mentioned above there are published cut-offs for what is considered excess urine production. Urine production is not often measured by owners but a concurrent change in water consumption is noticed in most instances and this can be measured. I typically ask owners to measure this over several days by providing their pet with a known quantity of water and then subtracting what is left at the end of the day. While it might be ideal to classify animals as polyuric and polydipsic by the amount of urine produced and water consumed, respectively, if the owner notices a change then I consider it significant and worth investigation.

A urinalysis should be performed on a free catch sample from home. This allows evaluation of urine specific gravity without the effects of transportation, stress and hospitalization on water consumption. In general, if the specific gravity is > 1.025 polyuria is unlikely. Animals that are persistently isosthenuric (1.008 – 1.012) are likely to have chronic kidney disease but many causes of polyuria can result in isosthenuria, hyposthenuria or minimally concentrated urine so it should be a repeatable finding. Persistent hyposthenuria is seen most often with hyperadrenocorticism, psychogenic polydipsia and central diabetes insipidus. It is also important to realize that central diabetes insipidus is extremely rare and urine can be either isosthenuric or hyposthenuric.

Patient history, signalment and a complete physical examination can reveal clues as to the cause of the polyuria. It is important to eliminate any possible medications that may cause polyuria. With most diseases mentioned there are other signs, in addition to polyuria, present. Animals with diabetes mellitus also display polyphagia and weight loss. Dogs with hyperadrenocorticism may have changes in appearance (pot belly, muscle wasting, endocrine alopecia) and concurrent polyphagia. Dogs and cats with chronic kidney disease may have weight loss and signs of uremia. An intact female that was in estrus in the last 2 months is a candidate for pyometra. Dogs with hepatic insufficiency might also display other signs of hepatic encephalopathy. Intestinal signs and weakness are common with hypoadrenocorticism. An older, thin cat with polyphagia and poor coat should be evaluated for hyperthyroidism. An older dog with a perianal mass might have an anal sac adenocarcinoma and hypercalcemia.

In addition to a urinalysis, a CBC, biochemical profile, urine culture, and serum thyroxine level (cats) will screen for most causes of polyuria. These tests evaluate for polycythemia, diabetes mellitus, chronic kidney disease, pyelonephritis, hyperadrenocorticism, typical hypoadrenocorticism, hepatic disease, hypercalcemia, hypokalemia, hyperaldosteronism, and renal glycosuria. It is important to remember that urine concentrating ability is usually lost prior to the development of azotemia in dogs and cats so just because BUN and creatinine are normal on the biochemical panel does not mean there is not kidney disease. Proteinuria and high normal BUN and creatinine may support kidney disease as a cause of the polyuria. In these cases additional measures of glomerular filtration rate (iohexol clearance, creatinine clearance, nuclear scintigraphy) may be required to eliminate kidney disease as a cause of polyuria. In addition, there are a few dogs with hyperadrenocorticism that may have normal liver enzymes which is why a screening test for hyperadrenocorticism is recommended even in the absence of the classic pattern in liver enzyme elevations. Congenital portosystemic vascular anomalies have variable liver enzymes as well. Bile acids are a more sensitive test for the diagnosis of these disorders and are recommended, particularly in younger animals.

If the tests described above fail to identify a cause diagnostic imaging is recommended. This will help identify a paraneoplastic polyuria. This is typically done with 3 view thoracic radiographs as well as an abdominal ultrasound. Abdominal ultrasound may be useful in evaluating for other disease described above such as chronic kidney disease, pyelonephritis, hyperadrenocorticism, hypercalcemia, hyperaldosteronism, pyometra, and portosystemic vascular anomalies.

Once the above conditions have been ruled out the primary differentials are psychogenic polydipsia, central diabetes insipidus and nephrogenic diabetes insipidus. The modified water deprivation test is utilized to differentiate between these three disorders. This test determines whether the body can release endogenous vasopressin in the face of dehydration or hypovolemia and whether the kidneys are capable of responding to vasopressin. The modified water deprivation test does not discriminate between primary and secondary nephrogenic diabetes insipidus but primary nephrogenic diabetes insipidus is a rare congenital disease due to a lack of vasopressin receptors in the kidney. Secondary nephrogenic diabetes should have been ruled out with the tests above but this is often not the case. A diagnosis of nephrogenic diabetes in a water deprivation test usually suggests the primary disorder causing a secondary nephrogenic diabetes insipidus was overlooked.

The test starts with the owners recording water consumption over several days to get an idea how much water is consumed. Then over about 5 days water consumption is decreased to 100 ml/kg/day with the intent of eliminating the influence of medullary washout on urine concentrating ability. It is important to offer water in aliquots throughout the day so it is not all consumed at once and the animal predisposed to dehydration. In addition, animals need to be monitored for signs of dehydration and hypernatremia including lethargy, depression and a poor appetite throughout the test and if these develop the test should be stopped and gradual reintroduction of water instituted.

Once the animal is consuming 100 ml/kg/day the actual test begins with a 12 hour fast and admission to the hospital. The urinary bladder is emptied and the animal weighed. Baseline laboratory evaluation (including kidney values, electrolytes and urine specific gravity) is performed. Measurement of baseline serum and urine osmolality is ideal but this is not readily available in most situations. If at this point in the test, urine specific gravity is > 1.030 there is no need to proceed with the test and psychogenic polydipsia or medullary washout is diagnosed. In addition, if hypernatremia or azotemia is present the test should be discontinued. Every hour the urinary bladder is emptied and the patient weighed. Periodically, kidney values and sodium are checked. The goal is approximately 5% dehydration (5% weight loss) at which time vasopressin release should be maximized. This may take < 12 hours with either form of diabetes insipidus but can take over 24 hours with psychogenic polydipsia. The idea is that dehydration and hypovolemia should stimulate vasopressin release from the pituitary so if vasopressin release is normal and the kidneys can respond then urine should be concentrated. Vasopressin levels can also be tested at this point. If at this point the urine specific gravity is > 1.030 then psychogenic polydipsia is diagnosed.

If urine is not maximally concentrated then vasopressin is administered, the urinary bladder emptied and urine specific gravity checked more frequently. There are different forms of natural and synthetic vasopressin (aqueous vasopressin, desmopressin acetate) that are administered via different routes (IV, IM, SC) with different recommendations for monitoring (q 15 to 30 mins for up to 8 hours). An increase in urine specific gravity following administration of vasopressin implies a deficiency in vasopressin secretion but renal responsiveness thus central diabetes insipidus. With complete central diabetes insipidus animals will not concentrate after dehydration but administration of vasopressin will cause a dramatic increase in urine osmolality and specific gravity. With partial central diabetes insipidus, animals will become more concentrated after dehydration but ot to 1.030. With vasopressin these animals will have a noticeable but more modest increase in urine osmolaity and specific gravity. No response or minimal response to vasopressin implies that although vasopressin is present the kidneys can't respond so nephrogenic diabetes insipidus is present. These animals may concentrate some after dehydration but there is little improvement with vasopressin. Unfortunately the water deprivation test can take up to 3 days to complete and the results are not always decisive.

Summary

The diagnosis of polyuria first involves the differentiation between polyuria and lower urinary tract disease. Polyuria is almost always accompanied by polydipsia and the approach to diagnosis of the underlying disorder is the same. It is important to perform a complete and orderly evaluation of potential causes because primary central diabetes insipidus is extremely rare.

References

Feldman EC. Polyuria and Polydipsia in Textbook of Small Animal Veterinary Internal Medicine. 7th ed. Ettinger SJ, Feldman EC (eds). 2010 Elsevier pp 156 – 159.

Feldman EC, Nelson RW. Water Metabolism and Diabetes Insipidus in Canine and Feline Endocrinology. 3rd ed. Feldman EC, Nelson RD (eds). 2004 Saunders pp 2 – 44.